Dr. Andrei Iagaru
Dr. Walter G. Park
Principal Investigator (contact): Andrei Iagaru, M.D.
Institution: Stanford University
Principal Investigator: Walter G. Park, M.D., M.S.
Institution: Stanford University
Synopsis of Research and Network Resources
Title of the PCDC Project
MOLECULAR IMAGING METHODS FOR THE DETECTION OF PANCREATIC DUCTAL ADENOCARCINOMA
Because patients diagnosed at earlier stages of pancreatic ductal adenocarcinoma (PDAC) have higher survival rates, imaging modalities that enable earlier detection are needed. Such novel imaging platforms will complement the development of any non-invasive biomarkers for PDAC by localizing early stage neoplasms.
Description of the Project
Our project, "Molecular Imaging Methods for the Detection of Pancreatic Ductal Adenocarcinoma", is a multi-disciplinary collaboration at Stanford that builds on expertise on molecular imaging strategies for the early detection of PDAC.
We have previously studied 2 different molecular imaging approaches for early detection of cancer that are proposed in our project. The first approach involves using micron-sized microbubbles as an ultrasound contrast agent. These microbubbles can be modified by incorporating specific ligands into the microbubble shell to bind to specific molecular targets of PDAC. Combined with transabdominal and/or endoscopic ultrasound these targeted agents may improve the sensitivity and specificity for visualizing smaller PDAC and potentially high-grade precursor lesions. Dr. Willmann’s research team has developed a targeted microbubble incorporating vascular endothelial growth factor receptor type 2 (VEGFR2; also called kinase insert domain receptor, KDR) and validated its use in a transgenic mouse model of PDAC development. Using this model, PDAC can be detected with an average 26.8-fold higher imaging signal intensity compared to normal wild-type pancreas using this KDR-targeted clinical grade MB contrast agent. In particular small (<3 mm) tumors showed the highest KDR-specific ultrasound imaging signals and tumors down to approximately 1 mm in size could be reliably visualized in this preclinical study. First in human clinical pilot trials using this KDR-targeted contrast enhanced ultrasound (CEUS) in patients with breast, ovarian, and prostate cancer have been performed and have demonstrated safety, feasibility and early efficacy.
The second approach focuses on a specific positron emission tomography (PET) tracer for PDAC. Current clinical practice commonly relies on computed tomography and/or  FDG PET to assist in PDAC staging and recurrence. These modalities, however, have limited ability to discriminate non-specific inflammatory changes from cancer. Under the leadership of Dr. Sam Gambhir (co-investigator), our group has developed a PET tracer that selectively binds, with single-digit nanomolar affinity, to integrin αvβ6, a cell surface receptor that is over-expressed in PDAC. This new PET tracer is based on the engineered cystine knot peptide R01-MG, which has demonstrated rapid, high and specific tumor uptake and excellent tumor-to-normal tissue ratios in mouse models of integrin αvβ6-positive PDAC cancers. In preclinical animal studies, the PET tracer targeted to integrin αvβ6, called [18F] FP-R01-MG-F2, has shown rapid, high and sustained tumor uptake and retention, low uptake in the liver and pancreas, and rapid clearance from most normal tissues. Excellent tumor-to-normal tissue ratios clearly distinguished tumor from normal tissues in preclinical studies. Collectively, these support the translation of [18F] FP-R01-MG-F2 as a promising new PET tracer for better detection of PDAC. Our group has recently received an FDA eIND (# 126379; Gambhir) for [18F] FP-R01-MG-F2 to allow first-in-human clinical studies on its biosafety/dosimetry in humans, and then, to assess its ability to visualize PDAC.
Our project has 4 aims. Aim 1 is to collaboratively work with other units of the consortium in developing a standardized annotated bio-repository with longitudinal follow-up of patients at high risk for developing PDAC. These include patients with pancreatic cysts and those with established genetic mutations and/or family history for PDAC. Aim 2 is to perform first-in-human clinical trials to determine the feasibility, efficacy, and safety of KDR-targeted molecular CEUS in patients with resectable PDAC. Part of this aim will study novel coherence beamforming techniques to optimize the signal intensity ratio with targeted microbubble imaging. Aim 3 is to perform a first-in-human clinical trial to determine the feasibility, efficacy, and safety of αvβ6-targeted PET-CT imaging in patients with PDAC. Aim 4 will build upon the results of Aim 2 and begin prospective pilot clinical trials using KDR-targeted molecular CEUS in patients at high risk for PDAC.
Resources for Sharing
Under IRB approved protocols, we have been banking biospecimens from patients with a spectrum of pancreatic disorders. We have approximately banked 400 pancreatic cyst samples with 200 having histological correlation. We have approximately 50 secretin-stimulated pancreatic fluid samples from patients with suspected chronic pancreatitis (CP), established CP, PDAC, and at high risk for PDAC. We have approximately 150 serum/plasma samples from patients with acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. With the proposed aims, we will be systematically collecting biospecimens (serum, plasma, cyst fluid, pancreatic fluid) from patients at high risk for PDAC and resectable PDAC.
Opportunities for Collaboration
We welcome all collaborative opportunities that will advance the goal of the consortium. These opportunities include resource sharing of biospecimens to develop and validate promising non-invasive biomarkers to integration of promising biomarkers to our planned molecular imaging trials.